Browsing by Author "Liu, Yun; Fox, Joseph M"
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Item Conformationally Strained trans-Cyclooctene (sTCO) Enables the Rapid Construction of F-18-PET Probes via Tetrazine Ligation(Ivyspring International Publisher, 4/12/16) Wang,Mengzhe; Svatunek,Dennis; Rohlfing,Katarina; Liu,Yu; Wang,Hui; Giglio,Ben; Yuan,Hong; Wu,Zhanghong; Li,Zibo; Fox,Joseph; Mengzhe Wang, Dennis Svatunek, Katarina Rohlfing, Yu Liu, Hui Wang, Ben Giglio, Hong Yuan, Zhanghong Wu, Zibo Li, and Joseph Fox; Liu, Yun; Fox, Joseph MThe bioorthogonal reaction between tetrazines and trans-cyclooctenes is a method for the rapid construction of F-18 probes for PET imaging. Described here is a second generation F-18-labeling system based on a conformationally strained trans-cyclooctene (sTCO)-a dienophile that is approximately 2 orders of magnitude more reactive than conventional TCO dienophiles. Starting from a readily prepared tosylate precursor, an F-18 labeled sTCO derivative (F-18-sTCO) could be synthesized in 29.3 +/- 5.1% isolated yield and with high specific activity. Tetrazine ligation was carried out with a cyclic RGD-conjugate of a diphenyl-s-tetrazine analogue (RGD-Tz) chosen from a diene class with an excellent combination of fast reactivity and stability both for the diene as well as the Diels-Alder adduct. For both the tetrazine and the sTCO, mini-PEG spacers were included to enhance solubility and improve the in vivo distribution profile of the resulting probe. Extremely fast reactivity (up to 2.86 x 10(5) M(-1)s(-1) at 25 degrees C in water) has been observed in kinetic studies in the reaction of sTCO with diphenyl-s-tetrazine derivatives. A kinetic study on sTCO diastereomers in 55:45 MeOH:water showed that the syn-diastereomer displayed slightly faster reactivity than the anti-diastereomer. An F-18-sTCO conjugate with RGD-Tz demonstrated prominent and persistent tumor uptake in vivo with good tumor-to-background contrast. Unlike most radiolabeled RGD peptides, the tumor uptake of this PET agent increased from 5.3 +/- 0.2% ID/g at 1 h post injection (p.i.), to 8.9 +/- 0.5% ID/g at 4 h p.i., providing evidence for prolonged blood circulation. These findings suggest that tetrazine ligations employing F-18-sTCO should serve as a powerful and general platform for the rapid construction of peptide or protein derived PET agents.